Over the years, several methods of administering therapeutic substances to mammals have been proposed. Although the oral route of administration is highly desirable from a patient compliance standpoint, the route is not practical for a large number of therapeutic compounds. Consequently, parenteral administration of many compounds via the intravenous or intramuscular route must be employed. Even when these routes are employed, there often problems associated with administration of the medicinal. This is especially true when the compound is either poorly soluble or is rapidly degraded or eliminated in vivo.
As an outgrowth of the above, there has been significant effort directed to developing useful transport mechanisms for effectively delivering therapeutic compounds to patients in need of treatment. More recently, interest has been shown in preparing prodrug-based transport forms in order to solve problems such as poor solubility associated with particular therapeutic compounds. For example, commonly-assigned U.S. Pat. No. 5,880,131 discloses using amino acid spacer groups with poly(ethylene glycol) ester prodrugs of 20-(S)-camptothecin, an anti-cancer alkaloid having a highly hindered OH at the 20-position. Esterification of the 20-OH group was accomplished in high yield by employing diisopropyl carbodiimide (DIPC) in the presence of 4-dimethylaminopyridine (DMAP). The reaction, however, is accompanied by substantial racemization for each stereoisomer, usually about 25% for t-Boc (L)-alanine and about 40% for t-Boc-(D)-alanine. In cases where conservation of chiral purity is necessary or desired, increased costs are incurred by efforts to isolate the desired diasteriomer because the artisan must subject the intermediate to one or more recrystallizations which also drive down the final yield. It would therefore be highly desirable to eliminate crystallization steps, especially if large scale quantities are required.
Recent advances in the acylation of tertiary alcohols which produce high yields of esters employ symmetrical carboxylic acid anhydrides and the readily-available Lewis acid catalyst scandium triflate Sc(OTf).sub.3. This procedure, however, has been determined to be unsuitable for acylating hindered tertiary alcohols with mixed anhydrides of complex acids. The same authors later reported in Synlett.
September 1996, 839-841 that Sc(OTf).sub.3 and a related catalyst were extremely active acetalization catalysts which afforded highly diastereoselective reactions. No information was provided regarding acylation-type reactions.
Gibson, et al. in J. Org. Chem. 1994, 59, 7503-7507 reported that high yields of t-butyl esters were possible with little or no racemization. However this approach has been deemed to be not convenient by some practitioners because it entails the multi-step synthesis of a water-soluble carbodimide that must be converted to a t-butyl isourea using a cuprous chloride catalyst.
In view of the foregoing, synthesis of esters of tertiary alcohols with complex acids, especially amino acids, while maintaining chirality remains a challenging task. A need exists, therefore, for an improved method of forming esters of tertiary alcohols, especially when stereoselectivity in esterification of compounds containing a tertiary alcohol is required. The present invention addresses this need.